The Preparation And The Pharmacokinetic Study Of Linagliptin Gel

Diabetes is one of the three major epidemics in the world,and diabetic gastroparesis is a common complication.It is difficult for patients to have meals and take medicine due to uncontrolled blood glucose.Transdermal administration can effectively control blood glucose on the basis of reducing the burden of gastrointestinal tract.As a first-line hypoglycemic drug,linagliptin has high safety,even in patients with renal injury,there is no need to adjust the dosage.Therefore,in this project,based on the importing of linagliptin document approval by Chinese Food and Drug Administration and some related patents,the primary formulation of gel containing 0.1% active ingredients,Carbomer 980,diethylene glycol mono ethyl ether,glycerol,ethyl benzoate and triethanolamine were initially prepared,and a gel was prepared according to different proportions of glycerol,ethyl benzoate and triethanolamine.In the first part,according to the physical and chemical properties of linagliptin,combined with the requirements of China Pharmacopoeia 2020 edition of gel and the proportion of the prescription and accessories in the patent,the best excipients were obtained by taking the gel layering,viscosity and ductility as the evaluation criteria.In order to improve the insoluble solubility of gelatin and add diethylene glycol mono ethyl ether.Then,in order to control the safety and effectiveness of the new gel,we set up an index for evaluating the quality of the gel.Combined with the general principles of the gel in the 2020 edition of China Pharmacopoeia,the appearance,loading capacity,p H and uniformity were evaluated and the evaluation criteria were established.High quality liquid chromatography was used to detect the related substances and contents of self-made gel and API.The penetration test of Leigh Glenn Dean gel,Lee Teuk gel penetration rate was detected according to the methodology established by Leigh Glenn Dean quality control.The results showed that the release of legletine gel had a sustained release effect in vitro,and the transmittance increased significantly after 4 hours.Under extreme conditions,experiments were conducted on Leigh Glenn Dean’s influencing factors.The p H,homogeneity,appearance and drug content in strong light,high temperature and high humidity environment were investigated.The results showed that linagliptin gel was affected by strong light and high temperature,and should be stored avoid light and shade.The second part,According to Leigh Gerrit’s self-made gel,according to the guideline of non clinical safety evaluation of drugs in 2015 by changing the dosage form and changing the way of administration in the US FDA,we used rats as the experimental subjects to carry out skin allergy test and eye irritation test.Compared with the positive control group,the skin of Lee Teuk rats had good adaptability to self-made gellet gel,and no strong irritation and mild stimulation could be achieved in January.However,the reaction of rat eye to linagliptin and homemade gel was larger.In the third part,in order to study the drug metabolism of linagliptin in vivo,rats were used as experimental animals to establish an analytical methodology for the determination of linagliptin in plasma by high performance liquid chromatography.The most suitable wavelength was selected to detect the drug content in plasma and eliminate the interference of endogenous substances.In view of the problem that linagliptin is closely combined with plasma and difficult to release,alkaline substances were added to maintain molecular stability.By using liquid-liquid extraction method,the mixed extraction of single reagent and multi reagent was tried.Finally,ethyl acetate was the most suitable extractant,and the recovery rate was more than 80%.According to established methodology,pharmacokinetic experiments were carried out in rats.Compared with the data of drug metabolism after gastric lavage and transdermal administration,the results showed that the self prepared gel could prolong the half-life of oral administration compared with oral administration.Abnormal peak shape was found in animal metabolism experiment,and it was preliminarily determined that it was a derivative with similar structure to linagliptin after collection and analysis.